Skin has a myriad of functions, including protection against pathogens and excessive water loss, insulation, temperature regulation, sensation and protection of vitamin B folates. As such, impairment or ailments of the skin may significantly affect the health of a person or animal. Furthermore, such impairments or ailments may cause irritation, pain or other discomfort and may undesirably affect the person or animal's physical appearance.
An important aspect for the treatment of many skin impairments or ailments, including wounds and burns, is the control of infection, which may facilitate the healing process. Topical medicaments are commonly used tools to protect wounds and other skin ailments from infection. Antimicrobial agents are often incorporated into topical medicaments and wound dressing to treat and prevent infection. However, there may be disadvantages associated with use of antimicrobial agents. It has been observed that an increasing number of pathogens have developed resistance to conventional antibiotic treatments. According to statistics, antibiotic-resistant pathogens are the primary reason for a majority of all lethal nosocomial infections. See Robson et al., Surg. Clin. N. Am. 77, 637-650 (1977). Furthermore, many antimicrobial agents not only kill pathogens, but also impose a threat to the proliferating granulation tissue, fibroblasts and keratinocytes that may help with the wound healing process. Additionally, some antimicrobial agents may cause allergic reactions in some patients.
It is known that nitric oxide possesses a broad-spectrum of antimicrobial activity and may be used as an alternative to conventional antibiotics for drug resistant bacteria. Furthermore, some recent studies have demonstrated that nitric oxide may also play an important role in the wound healing process by promoting angiogenesis through stimulation of vascular endothelial growth factor (VEGF) and increase fibroblast collagen synthesis. See Schaffer M R, et al., Diabetes-impaired healing and reduced wound nitric oxide synthesis: A possible pathophysiologic correlation. Surgery 1997; 121(5):513-9; and Shi H P, et al., The role of iNOS in wound healing. Surgery 2001; 130 (2):225-9. Thus, nitric oxide presents a promising addition and/or alternative to the conventional antibiotic treatments. Furthermore, nitric oxide has been shown to have other beneficial properties, including reducing inflammation and participation in wound healing biochemical cascades. Unfortunately, the relationship between exogenously applied concentrations of nitric to promote healing, mediate inflammation, or treat infection are not clearly understood.
Nitric oxide is a gas at ambient temperature and atmospheric pressure, and it has a short half-life in a physiological milieu. Several small molecule nitric oxide donor prodrugs have been developed which have contributed greatly to the understanding of nitric oxide in a number of disease states. However, due to their issues with stability, indiscriminate NO-release, monotypical nitric oxide release kinetics, and inability to target specific tissue types, optimal solutions for administering nitric oxide outside of its gaseous form have not yet been achieved. Reproducibly delivering the correct levels of nitric oxide for a given therapeutic indication is critical because the release of large amounts of nitric oxide may be toxic or create undesirable side effects such as an increase in inflammation. Therefore, it has been challenging to use nitric oxide for topical therapeutic applications, particularly for reproducibly delivering nitric oxide in a controlled manner from vehicles capable of targeting tissue structures.
As an example, previous investigators have explored the use of topical formulations containing an alkali nitrite source in combination with ascorbic acid or other organic acid, that upon admixture or mixing create a rapid bolus of nitric oxide release. While the antimicrobial efficacy of nitric oxide released via this approach has been shown, it may also result in decrease in angiogenesis, increase in inflammation and unwanted toxicity. Thus, the need exists for topical treatments and medicaments that can release nitric oxide by a controlled delivery method.